Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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Variant: NM_000314.6(PTEN):c.-975G>C

CA000654

127685 (ClinVar)

Gene: PTEN

Condition: PTEN hamartoma tumor syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: d5ebdbde-0541-439f-8bbb-2234f7aa3636

HGVS expressions

NM_000314.6:c.-975G>C

NM_000314.6(PTEN):c.-975G>C

NC_000010.11:g.87863494G>C

CM000672.2:g.87863494G>C

NC_000010.10:g.89623251G>C

CM000672.1:g.89623251G>C

NC_000010.9:g.89613231G>C

NG_007466.2:g.5057G>C

NG_033079.1:g.4944C>G

NM_000314.5:c.-975G>C

NM_001304717.2:c.-456G>C

NM_001304718.1:c.-1680G>C

ENST00000371953.7:c.-976G>C

ENST00000610634.1:c.-1078G>C

Likely Benign

BS1 BP5

PS3 PS4 PS2 PS1 PP2 PP3 PP1 PM4 PM1 PM5 PM2 PM6 PVS1 BA1 BS2 BS3 BS4 BP4 BP2 BP7

Evidence Links 1

Expert Panel

PTEN VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

PTEN VCEP

PTEN c.-975G>C (g.89623251G>C) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). BS1: Allele frequency of 0.006 (0.6%, 21/3466 alleles) in the European (Finnish) subpopulation and 0.002 (0.2%, 30/14,976) in the European (Non-Finnish) subpopulation of the gnomAD cohort. (PMID 27535533) BP5: Variant found in multiple cases with alternate molecular basis for disease. (internal laboratory contributors SCV000187238.1, SCV000149489.5)

BS1

Variant is found in 55/30846 control chromosomes at a frequency of 0.0017831. Found in 21/3466 individuals of European/Finnish ancestry and 30/14976 European/non-Finnish ancestry. Allele frequency fall in the range of 0.001 up to 0.01 in a population with > 2000 alleles and variant is present in > 5 alleles. FH: I agree

BP5

Internal data from GeneDx shows variant in multiple cases with other pathogenic gene mutation. Some information about personal or family history and overlap is unlikely. (1) proband, BRCA1+, no cancer fam hx of breast, uterine ovarian, pancreatic, bile duct, stomach (2) proband: breast ca and MSH6+, fam hx of ovarian, panc, lung (3) proband, no cancer and BRCA1+, fam hx: breast, ovarian, esophageal (4) proband TNBC and BRCA2+, fam hx: breast, prostate (5) proband no cancer but EPCAM/MSH2+, fam hx: colon, endometrial (6) proband had breast and ovarian and BRCA1+, fam hx: prostate and leukemia (7) proband had small bowel ca and MSH6+, fam hx: NA (8) kid with macrocephaly, DD, dysmorphic and NSD1+, negative fam hx (9) proband no cancer and BRCA1+ family hx: breast, prostate, lung (10) proband with colon x 2 and MSH2+ fam hx: colon, ovarian, breast (11) proband with TNBC and MSH6+, fam hx: breast and panc ca. FH (BP5): internal data for observations with a pathogenic variant in a different gene explaining the patient's phenotype: 1. MSH2 mutation. MSH2/MSH6-deficient CRC at 62y. Family hx: mother CRC dx 3X 30s-60s; MGM OV 40s. 2. proband dx with an extra-adrenal paraganglioma @21 SDHB VLP.

PS3

Heikkinen et al (2011) analyzed the affects of promoter variants in PTEN and breast cancer progression and survival. The presence of this variant is associated with poor survival in breast cancer patients. MPerpich entry.

PubMed:22171747

PS4

25 internal cases from Charis Eng's lab all with CC scores less than 18 so none meet criteria for PS4, PS4_moderate, PS4_supporting.

PS2